Therapeutic composition for the treatment of angina pectoris and method



United States Patent G 3,063,960 THERAPEUTIC COMPOSITION FOR THE TREAT-MENT F ANGINA PECTORIS AND METHOD Travis Winser, 4641 Wiishire Blvd LosAngeles 5, Calif. No Drawing. Filed Jan. 5, 1960, Ser. No. 498 3 Claims.(Cl. 167-65) This invention relates to a new and novel therapeuticcomposition for use in the treatment of angina pectoris and to a methodof treatment.

Angina pectoris is a disease marked by paroxysmal thoracic pain, withsuffocation and syncope which is most frequently due to anoxia of themyocardium. Anginal attacks are most often precipitated in patients byeffort and excitement. Any form of physical effort is contraindicated inmany patients who on occasions can experience up to 50 or even moreattacks per day. Classic therapy for this disease has been rest, theadministration of nitroglycerine for immediate relief of acute attacksand the use of longer acting nitrates such as pentaerythritoltetranitrate to reduce the frequency and severity of anginal attacks.

There has long been a need for an effective composition and method fortreating this disease which will not only reduce the frequency andseverity of attacks but will also permit increased physical activity forthose patients who, under classic therapy, must remain virtuallybed-ridden.

It is, therefore, a particular object of the present invention toprovide a new and improved therapeutic composition which is effective inthe treatment of angina pectoris.

Other objects and the advantages of this invention will appearhereinafter.

It has now been found that the administration of a combination of along-acting effective organic nitrate and a nontoxic monoamine oxidaseinhibitor to patients suffering from angina pectoris is remarkablyeffective in mitigating clinical symptoms and in affording relief fromthe manifestations of this disease.

It has recently been discovered that the enzyme monoamine oxidase has asignificant effect on the activity of the central nervous system and inother areas of the body in that this enzyme promotes the destruction ofserotonin and catechol amines. It has been observed that theadministration of an inhibitor of monoamine oxidase results in astimulation of the central nervous system brought about by the increasein the concentra tion of serotonin and catechol amines. The presentinvention is based upon the discovery that a combination of along-acting effective organic nitrate with anon-toxic monoamine oxidaseinhibitor is remarkably effective in the treatment of angina pectoris.

The term a long-acting effective organic nitrate as used throughout thespecification and in the claims refers to any of the known long-actingorganic nitrate vasodilators which have been used in the treatment ofangina pectoris. Such compounds have a relatively slow onset of activitybut are effective for several hours after administration. 'Bhey) differ,therefore, from fast-acting organic nitrates such as nitroglycerin.Useful long-acting effective organic nitrates which may be used incombination with a non-toxic effective monoamine oxidase inhibitor arepentaerythritol tetranitrate, 1,4:3,6- dianhydrosorbitol 2,5-dinitrate,triethanolamine trinitrate biphosphate and the like. Pentaerythritoltetranitrate is preferred.

Any non-toxic compound which is an effective inhibitor of monoamineoxidase may be used in the therapeutic compositions of the presentinvention. It is possible, by means of a well accepted pharmacologicaltest, to determine readily whether a particular compound is effectiveICC as an inhibitor of this enzyme. This test is based on the fact thatwhen mice are pre-treated with an effective monoamine oxidase inhibitorand are thereafter challenged with resperpine they exhibitmanifestations of ex citation and aggressiveness. Where the compound inquestion is ineffective as an inhibitor of monoamine oxidase no suchmanifestations occur following 'resperpine challenge.

The term an effective monoamine oxidase inhibitor, as used throughoutthe specification and in the claims, refers to a compound which iseffective at a dosage of mg./ kg. of body weight or less in mice asdetermined by the following test procedure. The compound is administeredat graded doses intraperitoneally to a series of mice. Three to ninehours after administration each mouse is challenged with reserpine at a'dosage of 1 mg./kg. of body weight, administered intravenously. If themouse exhibits manifestations of excitation and aggressiveness at adosage of 100 mg./kg. or less, the compound in question is an effectivemonoamine oxidase 1nhibitor. Where the compound is administered as apharmaceutically acceptable acid salt, dosages are calculated based onthe free base.

It is also an essential requirement vthat the compound be non-toxic inrelation to the effective dose, a property which may be readilyevaluated by well-known pharmacological test procedures.

Non-toxic, effective monoamine oxidase inhibitors which may be used incombination with a long-acting effective organic nitrate in accordancewith this invention are preferably hydrazine derivatives, for example:

1-isonicotinyl-2-isopropylhydrazine which is reported by E. A. Zeller etal., Proc. Soc. Exptl. Biol. Med 81, 459 (1952), as having in vivoactivity in inhibiting monoamine oxidase and which has been usedclinically as an antidepressant;

N-benzyl-fi-(isonicotinylhydrazino) propionamide and compounds relatedthereto as described in US. Patent No. 2,894,972;

1-benzyl-2-(5 methyl-3-isoxazolylcarbonyl) hydrazine which has beentested clinically in depressed patients as reported by H. F, Darling etal., Dis. Nerv. Syst. 20, 269 (1959);

[3-Phenylisopropylhydrazine, a known inhibitor of monoamine oxidase asreported by Horita, J. Pharmacol. Exper. Therap. 122, 176 (1958);

Hydrazine derivatives of the structure Re where X is halogen, hydroxyl,alkoxy, alkyl or amino; A is -CH lower alkyl CH2'-CH2, OI and R1- and R2are hydrogen, lower alkyl or acyl as disclosed in copending applicationsSerial' Numbers 766,407, 766,408,- 766,409, 766,410, 766,413, all filedOctober 10,1958, of which 766,410 and 766,413 are now abandoned, and773,572, filed November 13, 1958;

Hydrazine derivatives of the structure lower alkyl where X is hydrogen,halogen, hydroxy or lower alkoxy and R is lower alkyl or c H Y where nis 2 or 3 and Y is hydroxyl, chloro, di-lower alkylamino, piperidino,piperazino, morpholino or pyrrolidino, as disclosed in 3 copendingapplication Serial Number 850,988 filed November 5, 1959.

The hydrazine derivatives enumerated above may also be used in the formof their non-toxic salts in formula-ting the compositions of thisinvention.

It has been found that the administration of ,B-phenethylhydrazine orits non-toxic acid salts in combination with the widely utilizedpentaerythritol tetranitrate is a particularly elfective method oftreating angina pectoris. The therapeutic compositions of the presentinvention comprise a combination in each dosage unit of about 3 to about50 milligrams of the non-toxic effective monoamine 'oxidase inhibitor(about 5 to about 25 milligrams with the preferred B-phenethylhydrazine)and about 2 to about 40 milligrams of the long-acting effective organicnitrate (about to about 40 milligrams with the preferred pentaerythritoltetranitrate). In the treatment of angina pectoris, the daily dosage isabout 9 to about 150 milligrams of the inhibitor (about to about 75milligrams with the preferred fi-phenethylhydrazine) and about 10 toabout 120 milligrams of the long-acting effective organic nitrate (about30 to about 120 milligrams with the preferred pentaerythritoltetranitrate). Vlhere the monoamine oxidase inhibitor is present as anon-toxic salt, the above milligram quantities refer to the amount ofthe free base resulting from hydrolysis of the salt form. The actualdosage schedule selected for any patient depends on the particularcompounds used, the tolerance of the patients to the compounds and theseverity of the angina pectoris condition.

In the treatment of angina pectoris the substituted hydrazine and thelong-acting eifective organic nitrate may be administered separately,but it is preferable that the two compounds be combined in a singledosage unit form. Any of the various dosage forms commonly employed intherapeutics may be used with core-type tablets being generallypreferred to prevent any possible chemical reaction between the activeingredients. In each dosage unit, the active ingredients are combinedwith suitable pharmaceutical diluents and carriers, depending on thephysical form of the dosage unit.

Data on a group of angina pectoris patients who have been studied in theclinic to determine the efiectiveness of administration ofpentaerythritol tetranitrate alone, ,B-phenethylhydrazine hydrogensulfate alone and the simultaneous administration of both compounds hasbeen obtained. In 70 percent of the patients, the best results in termsof reduction of severity and frequency of anginal attacks and theability of the patients to tolerate greater physical activity wereobtained with the simultaneous administration of both compounds.

The following example is given in order further to illustrate thepresent invention:

EXAMPLE A core-type tablet comprising as active ingredients acombination of phenethylhydrazine sulfate and pentaerythritoltetranitrate is prepared by the following procedure:

A. Tablet Cores A quantity of 12.9 grams phenethylhydrazine sulfate and174 grams mannitol are milled and passed through a number 1 screen. 6grams polyvinylpyrrolidone is dissolved in ml. isopropyl alcohol by mildheating and the screened mixture of phenethylhydrazine sulfate andmannitol is granulated with the resulting solution. The

granules are then regranulated with about 30 ml. isopropyl alcohol. Theresulting granules are dried and passed through a number 12 screen. Thescreened granules are then blended with 4 grams magnesium stearate and 4grams starch, and the resulting mixture is com pressed into 200milligram tablets.

B. Tablet Coating The tablets prepared as described in A above arecoated twice with pharmaceutical glaze (7 pound out) and the coatedtablets are dusted with talc. The dusted coated tablets are then coatedwith a gelatin-syrup solution and dusted again with a duster powdercomprising calcium carbonate, kaolin, talc, acacia and powdered sugar.The steps of coating with gelatin-syrup solution and dusting with dusterpowder are repeated several times. Tablets are then dusted repeatedlywith a mixture of 1 part pentaerythritol tetranitrate and 1.8 partsmannitol with the number of applications being sufficient so that uponassay each dusted tablet contains 20 milligrams pentaerythritoltetranitrate. The tablets are finally coated with a gelatin-syrupsolution, dusted with additional duster powder and finally coated with astandard polishing solution.

Each tablet contains 12.9 milligrams phenethylhydra- Zine sulfate(corresponding to 7.5 milligrams phen' ethylhydrazine base) and 20milligrams pentaerythritol tetranitrate.

It is understood that the foregoing detailed description is given merelyby way of illustration and that many variations may be made thereinwithout departing from the spirit of my invention.

Having described my invention, what I desire to secure by Letters Patentis:

l. A therapeutic composition in dosage unit form for use in thetreatment of angina pectoris which comprises a combination of about 10to about 40 milligrams of pentaerythritol tetranitrate and about 5 toabout 25 milligrams of a member selected from the group consisting offi-phenethylhydrazine and the non-toxic salts thereof.

2. A therapeutic composition according to claim 1 which comprises about7.5 milligrams of B-Phenethylhydrazine as the sulfate salt thereof andabout 20 milligrams of pentaerythritol tetranitrate.

3. A method of treating angina pectoris which comprises administeringdaily about 20 to about milligrams of a member selected from the groupconsisting of B-phenethylhydraziue and the non-toxic salts thereof andabout 30 to about milligrams of pentaerythritol tetranitrate.

References Cited in the file of this patent

1. A THERAPEUTIC COMPOSITION IN DOSAGE UNIT FORM FOR USE IN THETREATMENT OF ANGINA PECTORIS WHICH COMPRISES A COMBINATION OF ABOUT 10TO ABOUT 40 MILLIGRAMS OF PENTAERYTHRITOL TETRANITRATE AND ABOUT 5 TOABOUT 25 MILLIGRAMS OF A MEMBER SELECTED FROM THE GROUP CONSISTING OFB-PHENETHYLHYDRAZINE AND THE NON-TOXIC SALTS THEREOF.